ARMYDA-4 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study Prospective, multicenter, randomized, double blind trial investigating influence on PCI outcome of additional 600 mg clopidogrel load in patients on chronic therapy - “ARMYDA-Reload” Principal Investigators: Giuseppe Patti, Vincenzo Pasceri, Giuseppe Colonna Investigators: Antonio Montinaro, Leonardo Lassandro Pepe, Antonio Tondo, Laura Gatto, Fabio Mangiacapra, Francesco Ciccirillo, Andrea D’Ambrosio, Annunziata Nusca, Giordano Dicuonzo, Gennaro Sardella, Bibi NGuyen Chairman: Germano Di Sciascio

(%) ARMYDA-2 RESULTS Primary end-point 30-day Death, MI, TVR Circulation 2005;111: P= % 12%

Antiplatet effects of a 600 mg load on chronic clopidogrel Rx ADP (5  mol/L)-induced aggregation, % 600 mg clopidogrel Before load After load No prior clopidogrel N=20 N=20 Chronic clopidogrel N=20 N=20 P<0.001 P<0.001 P<0.001 Kastrati et al. Circulation 2004

PCI “reload” arm N= Patients on clopidogrel therapy with Stable angina or NSTE ACS undergoing coronary angiography Primary end point: Death, MI*, TVR 2 nd and 3 rd blood sample at 8 and 24 hours 30days Randomization Angiography Clopidogrel 600 mg re-loading ‡ N= st blood sample before PCI - CK-MB, troponin-I, myoglobin, CRP ARMYDA-4: Study design Placebo ‡ N= 234 PCI - placebo arm N= Hours pre-PCI * MI = >3 times UNL CK-MB ‡ On top of chronic therapy Medical Rx N= 62 CABG N= 42 N= 360

Inclusion criteria - Pts on chronic therapy with clopidogrel (> 10 days) with stable angina or non-STE ACS undergoing PCI Exclusion criteria - Primary PCI - Platelet count <70x10 3 /ml - Pts at high risk of bleeding - Coronary by-pass grafting in the previous 3 months ARMYDA-4

STUDY ENDPOINTS Primary endpoint  30-day incidence of death, MI, TVR (MI definition: post-procedural increase of CK-MB >3 times above UNL in patients with normal baseline levels of creatine kinase-MB) Secondary endpoints Any postprocedural increase of markers of myocardial injury above UNL (CK-MB, troponin I, myoglobin) Mean peak values of CK-MB, troponin I and myoglobin after intervention Occurrence of any vascular/hemorragic complications “Point of care” evaluation of platelet reactivity at different time points in the two arms

Age (yrs) Male sex (%) Diabetes mellitus (%) Hypertension (%) Hypercolesterolemia (%) Current smokers (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Clinical pattern (%) Non STE ACS Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%) 600 mg Clopidogrel reload N=180 Placebo N=180 P 65± (78) 56 (31) 136 (75) 142 (79) 36 (20) 54 (30) 88 (49) 16 (9) 67 (37) 78 (43) 55±7 180 (100) 171 (95) 65± (77) 59 (33) 149 (83) 142 (79) 34 (19) 57 (31) 77 (43) 13 (7) 70 (39) 67 (37) 55±7 180 (100) 168 (93) ARMYDA-4 Clinical Characteristics N=360 pts

P Vessel treated (%) Left main LAD LCx Right coronary SVG Chronic total occl. (>3 mo.)(%) Restenotic lesions (%) Lesion type B2/C (%) Multivessel intervention (%) Type of intervention (%) Balloon only Stent DES (%) 5 (2) 82 (40) 46 (22) 70 (34) 5 (2) 18 (10) 13 (7) 123 (59) 28 (15) 18 (10) 162 (90) 76 (42) 4 (2) 86 (40) 47 (22) 67 (31) 8 (3) 10 (5) 13 (7) 130 (61) 33 (18) 14 (8) 166 (92) 78 (43) mg Clopidogrel reload N=180 Placebo N=180 ARMYDA – 4 Trial Procedural features

ARMYDA-4 Trial Composite primary end-point (30-day death, MI, TVR) % 7 8 P=0.96

ARMYDA-4 Trial Individual events at 30 days 600 mg Clopidogrel reload Placebo 7 8 %

ARMYDA-4 Trial Secondary end points Post-procedural elevation of markers of myocardial injury above UNL % of patients 600 mg Clopidogrel re load Placebo P=0.98 P=

ARMYDA-4 Trial Secondary end points Post-PCI peak levels of markers of myocardial injury (CK-MB and Troponin-I) 600 mg Clopidogrel reload Placebo Peak value of CK-MB (ng/ml) Peak value of Tn-I (ng/ml) 5.6±7.55.3± ± ±0.87 P=0.90 CK-MB P= mg Clopidogrel reload Placebo Troponin-I 0.39±1.1

ARMYDA-4 Trial Secondary end points Bleeding rates 600 mg Clopidogrel reload Placebo %

211±66 166±60 217±66 183±68 177±71 153±65 208±68 173±69 199±64 178±62 174±65 146±63 Base Study PCI 2 hrs 6 hrs 24 hrs Drug Platelet reaction units (PRU) ARMYDA-4: Platelet aggregometry * P=0.2 * By Accumetrics Placebo Clopidogrel 600 mg Placebo Further load

 Results of the ARMYDA-4 trial indicate that a pre-PCI 600 mg loading dose does not confer additional clinical benefit in patients already receiving chronic therapy with clopidogrel  Point of care aggregometry testing shows no significant differences in platelet reactivity in the 2 arms  No increased bleeding risk is observed in the “reload” approach  Patients on chronic clopidogrel therapy can safely undergo PCI without need of further reload CONCLUSIONS

Several studies have demonstrated beneficial clinical effects of a 600 mg clopidogrel loading dose in patients undergoing percutaneous coronary intervention (PCI). Laboratory evidence suggests that an additional pre-PCI 600 mg loading further decreases platelet aggregation in patients already on chronic treatment with clopidogrel. However, there are no clinical data on the safety and efficacy of this strategy. BACKGROUND